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(Hypertension. 2006;47:1101.)
© 2006 American Heart Association, Inc.

Original Articles

Extrarenal Na⁺ Balance, Volume, and Blood Pressure Homeostasis in Intact and Ovariectomized Deoxycorticosterone-Acetate Salt Rats

Jens Titze; Friedrich C. Luft; Katharina Bauer; Peter Dietsch; Rainer Lang; Roland Veelken; Hubertus Wagner; Kai-Uwe Eckardt; Karl F. Hilgers

From the Department of Nephrology and Hypertension (J.T., K.B., R.L., R.V., K.-U.E., K.F.H.), Friedrich-Alexander-University, Erlangen-Nürnberg, Germany; Charité Campus Buch (F.C.L.), Franz Volhard Clinic, HELIOS Klinikum-Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; Institute of Biochemistry (P.D.), Charité Campus Benjamin Franklin, Berlin, Germany; Federal Research Centre for Nutrition and Food (H.W.), Kulmbach, Germany.

Correspondence to Jens Titze, Department of Nephrology and Hypertension, Loschgestr. 8, 91054 Erlangen, Germany. E-mail jens.titze{at}rzmail.uni-erlangen.de

	Abstract

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Water-free Na⁺ storage may buffer extracellular volume and mean arterial pressure (MAP) in spite of Na⁺ retention. We studied the relationship among internal Na⁺, K⁺, water balance, and MAP in Sprague-Dawley rats, with or without deoxycorticosterone-acetate (DOCA) salt, with or without ovariectomy (OVX). The rats were fed a low-salt (0.1% NaCl) or high-salt (8% NaCl) diet for 5 weeks. DOCA salt increased MAP (161±14 versus 123±4 mm Hg; P<0.05), and DOCA-OVX salt increased MAP further (181±22 mm Hg; P<0.05). DOCA salt increased the total body Na⁺ by &40% to 45%; however, water-free Na⁺ retention by osmotically inactive Na⁺ storage and by osmotically neutral Na⁺/K⁺ exchange allowed the rats to maintain the extracellular volume close to normal. DOCA-OVX salt rats showed similar Na⁺ retention. However, their osmotically inactive Na⁺ storage capacity was greatly reduced and only partially compensated by neutral Na⁺/K⁺ exchange, resulting in greater volume retention despite similar Na⁺ retention. For every 1% wet weight total body water gain, MAP increased by 2.3±0.2 mm Hg in DOCA salt rats and 2.5±0.3 mm Hg in DOCA-OVX salt rats. Because water-free Na⁺ retention buffered total body water content by 8% to 11% wet weight, we conclude that this internal Na⁺ escape buffered MAP. Extrarenal Na⁺ and volume balance seem to play an important role in long-term volume and MAP control.

Key Words: electrolytes • gender • water-electrolyte balance • hypertension, sodium-dependent

	Introduction

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Salt sensitivity describes a reproducible relationship between increasing salt intake and blood pressure.¹ Blood pressure may increase because of increased cardiac output, increased peripheral resistance, or both. Volume-dependent and volume-independent factors contribute. Volume-independent factors include autonomic nerve activity and molecules that modulate peripheral vascular resistance and heart muscle work. Volume-dependent aspects are based on extracellular fluid volume (ECV). Na⁺ is the major extracellular cation that osmotically acts to hold ECV water; the total body Na⁺ (TBNa⁺) has become synonymous for volume regulation.^2,3 Deoxycorticosterone-acetate (DOCA) decreases renal Na⁺ excretion and increases TBNa⁺ and total body volume. DOCA salt is a "prototype" model for salt-sensitive hypertension.⁴ Secondary renin–angiotensin–aldosterone system suppression,⁵ increased secretion of natriuretic peptides,⁶ and altered pressure natriuresis⁷ establish a new steady state between Na⁺ intake and Na⁺ excretion at a new blood pressure level. The kidneys escape the mineralocorticoid signal, and additional salt retention ceases, albeit with increased blood pressure.⁸ We showed recently that DOCA rats given 1% saline accumulated 4.75 mmol Na⁺.⁹ Only 20% of this Na⁺ load exerted osmotic activity and led to water retention, whereas the rest accumulated as water free by osmotically inactive Na⁺ storage and/or osmotically neutral Na⁺/K⁺ exchange. In Sprague-Dawley rats, we found that ovariectomy (OVX) reduced the osmotically inactive Na⁺ storage capacity with a high-salt diet.¹⁰ However, whether or not osmotically inactive Na⁺ storage attenuates blood pressure is unclear. We now investigated the osmotically inactive Na⁺ storage capacity in a prototype model of salt-sensitive hypertension with or without OVX. We hypothesized that water-free Na⁺ accumulation might buffer blood pressure by maintaining the ECV close to normal despite Na⁺ retention and that a reduced osmotically inactive Na⁺ storage capacity might augment DOCA salt hypertension.

	Methods

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Animal Experiments
Female Sprague-Dawley rats were obtained from Charles River (Sulzfeld, Germany) and used at age 7 to 8 weeks. OVX and DOCA pellet (50.0 mg/pellet, Innovative Research of America) implantation were performed under IP 100 mg/kg body weight (BW) methohexital anesthesia. Ovaries were excised via bilateral flank incisions. Pellets were replaced in all of the DOCA-treated rats after 3 weeks. The rats were fed either <0.1% NaCl [low salt (LS)] or 8% NaCl (salt) chow for 5 weeks and tap water ad libitum. They were not uninephrectomized. Rats were randomly assigned to 6 groups: group 1 (n=10), intact-LS; group 2 (n=10) intact-salt; group 3 (n=7), intact-LS-DOCA; group 4 (n=10), intact-salt-DOCA; group 5 (n=7), OVX-LS-DOCA; and group 6 (n=9), OVX-salt-DOCA. At the end of the experiment, the rats were anesthetized with 100 mg/kg BW methohexital, and the right femoral artery and femoral vein were catheterized. All of the rats received a 0.9% saline intravenous background infusion (3.5 mL/hour) and were placed into restrainers. Arterial lines were connected to Statham transducers and a Gould polygraph, and mean arterial pressure (MAP) was measured in the completely conscious animals 4 hours after the operation. Thereafter, blood samples were taken before the animals were killed.

Ashing Procedure
The skins, carcasses, and muscles were weighed [wet weight (WW)], then desiccated at 90°C for 72 hours [dry weight (DW)]. Because weights were unchanged with further drying, the difference between WW and DW was considered as tissue water content. The tissues were then ashed at 190° and 450°C for 24 hours at each temperature level, and the bones were sieved from the carcass ashes. The separated tissues were further ashed at 600°C for 48 hours and then dissolved in 10% HNO₃. Na⁺ and K⁺ concentration were measured by flame photometry (Model 3100, Perkin Elmer).

Data Analysis
Data are expressed as average±SD. Data from the various tissues Na⁺, K⁺, and water content were analyzed by multivariate analysis (general linear model). Post hoc tests were performed with the Bonferroni algorithm. The amount of osmotically active, osmotically inactive, and osmotically neutral Na⁺ accumulation was investigated from the relationship between changes of Na⁺ content and alterations of water content in total body, skin, bone, and rest carcass as described in detail in the online supplement available at http://www.hypertensionaha.org. We used SPSS software for statistical analysis (version 12.0).

	Results

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Compared with the controls, DOCA salt decreased WW and DW in the rest carcass and the skin, and bone ash mass. Compared with the controls and DOCA-treated rats, DOCA-OVX increased BW, carcass weight, and skin weight in both dietary protocols. Bone ash mass was higher in DOCA-OVX than in DOCA-alone rats but lower than in the controls (see online supplement). To adjust for the differences in BWs across the groups, we calculated the "relative" TBNa⁺ content (rTBNa⁺, all given as mmol/g DW), skinned and bone-removed rest carcass Na⁺, and relative skin Na⁺ in all of the rats (Table 1).

View this table: [in this window] [in a new window]   TABLE 1. Na+, K+, Water Content, and Blood Pressure in Control Rats and Intact or Ovariectomized DOCA Rats

DOCA increased the rTBNa⁺, whereas DOCA salt increased this value further, leading to an &40% TBNa⁺ excess compared with the controls. DOCA-OVX salt led to similar rTBNa⁺ excess that was not different from the DOCA salt group. Total body K⁺ (rTBK⁺) was not different between controls and the DOCA-alone group with both diets. The rTBK⁺ was not different between DOCA and DOCA-OVX rats given high salt. The Na⁺ and K⁺ content in the skinned and bone-removed carcasses showed pattern changes similar to rTBNa⁺ and rTBK⁺. Despite the massive increases in TBNa⁺, we found only moderate increases in the total body water content [(rTBW) all given as %WW] in DOCA salt rats. Salt increased rTBW in DOCA rats and increased rTBW further in DOCA-OVX rats, whereas no significant increases were observed in the controls. The relationship between rTBNa⁺ and rTBW was steep in control rats (Figure 1A). In rats receiving DOCA, this relationship had a flatter slope, indicating water-free Na⁺ retention. In DOCA-OVX rats, the relationship between rTBNa⁺ and rTBW was shifted right compared with the controls and left from intact DOCA-treated rats. This finding implies that the capacity to accumulate Na⁺ without water retention was reduced in DOCA-OVX rats.

View larger version (31K): [in this window] [in a new window]   Figure 1. (A) TBNa+ content (rTBNa+; mmol/g DW) and rTBW (mL/g WW) relationship was linear in control rats. In DOCA rats with or without salt, the relationship was shifted right, indicating water-free Na+ accumulation. DOCA-OVX led to a reduced water-free Na+ accumulation capacity, as indicated by the left shift compared with intact DOCA-treated rats. (B) In control rats, DOCA rats, and DOCA-OVX rats, changes in rTBW (% WW) were not correlated with MAP, although DOCA salt increased both rTBW and MAP in intact and OVX rats.

To quantify the differences in water-free Na⁺ retention capacity, we calculated the relationships (ratios) between Na⁺, K⁺, and the sum of the 2 cations (total effective osmolytes) with water in the tissues (Table 2). With DOCA, an increase in the ratio of TBNa⁺ per total body water was observed that increased further with DOCA salt, indicating water-free Na⁺ retention. Compared with intact rats, OVX decreased the TBNa⁺:water ratio in DOCA-treated rats (0.098±0.010 versus 0.106±0.009; P<0.05). DOCA-OVX decreased the ratio of TBNa⁺ per total body water back to the control level, whereas DOCA-OVX salt increased TBNa⁺ per total body water.

View this table: [in this window] [in a new window]   TABLE 2. Na+:Water, K+:Water, (Na++K+):Water, and MAP:Water Ratios in Control Rats and Intact or Ovariectomized DOCA Rats

We then quantified the absolute effect of DOCA salt and DOCA-OVX salt treatment on Na⁺ gain by calculating the contribution of osmotically active Na⁺ accumulation, osmotically inactive Na⁺ retention, and osmotically neutral Na⁺ retention (see online supplement for calculations). In the DOCA salt group, water-free TBNa⁺ gain relative to water was 3.18 mmol of which 1.41 mmol were balanced by rest carcass K⁺ losses. These relationships resulted in 1.77 mmol osmotically inactive Na⁺ storage in DOCA salt rats (Figure 2). Osmotically inactive Na⁺ storage occurred in the completely skinned and bone-removed rest carcasses and the skin, whereas the bone lost both Na⁺ and K⁺ relative to water in DOCA salt rats (Figure I, available online). The amount of osmotically active Na⁺ was 0.82 mmol in DOCA salt rats. In the DOCA-OVX salt group, TBNa⁺ gain relative to water was 2.57 mmol, of which 2.14 mmol were balanced by rest carcass K⁺ losses. These relationships resulted in 0.43 mmol of osmotically inactive Na⁺ storage in DOCA-OVX salt rats. This marked reduction in the osmotically inactive Na⁺ storage capacity in DOCA-OVX salt rats compared with intact DOCA salt rats was because of reduced Na⁺ storage in the rest carcass and a total loss of the skin Na⁺ storage capacity (Figure I). Similar to intact rats, DOCA-OVX rats lost bone Na⁺ and K⁺ relative to water. The amount of osmotically active Na⁺ retention was 1.51 mmol in DOCA-OVX salt rats.

View larger version (16K): [in this window] [in a new window]   Figure 2. Relationships in altered TBNa+ in DOCA salt-treated rats and OVX-DOCA salt rats compared with tap water control rats in terms of osmotically active Na+ (active), osmotically inactive Na+ (inactive), and osmotically neutral Na+/K+ exchange (neutral).

Thus, &80% of the Na⁺ gained in DOCA salt rats was either osmotically inactive or neutral (balanced by K⁺ loss) and could not have contributed to volume expansion (Figure 2). In DOCA-OVX salt rats, only &63% of the Na⁺ load was accumulated water free, whereas &37% were osmotically active. The reduced osmotically inactive Na⁺ storage capacity in DOCA-OVX rats was only partially compensated by water-free Na⁺ retention via osmotically neutral Na⁺/K⁺ exchange and, hence, led to augmented volume retention, despite similar Na⁺ accumulation in DOCA-OVX rats. Compared with control rats, DOCA salt rats accumulated 4.0 mmol Na⁺ (Figure 2). According to their serum Na⁺ and K⁺ concentration, this degree of Na⁺ accumulation should lead to 27-mL volume retention. We detected only 5-mL volume retention. DOCA-OVX salt rats accumulated 4.1 mmol of Na⁺. This degree of Na⁺ accumulation should lead to 28-mL volume retention. However, a 10-mL volume increase was observed. Thus, the compensatory increases in osmotically neutral Na⁺/K⁺ exchange could not rescue DOCA-OVX salt rats from augmented volume retention, despite similar Na⁺ retention compared with DOCA salt rats. This reduced osmotically inactive Na⁺ storage capacity, thus, led to augmented water retention despite similar Na⁺ retention in DOCA-OVX salt rats.

DOCA increased MAP even with low salt; high salt increased MAP further. This salt-sensitive blood pressure increase was exaggerated in the DOCA-OVX group (Table 1). We investigated the relationship between the total body fluid volume and MAP (mm Hg) in the rats (Figure 1B). In control rats, high salt did not increase rTBW or MAP, and we found no correlation between rTBW and MAP. In DOCA rats and DOCA-OVX rats, high salt increased both rTBW and MAP; however, rTBW and MAP were not correlated in DOCA salt rats, suggesting that rTBW increases did not invariably increase MAP. Furthermore, MAP in DOCA salt rats and DOCA-OVX salt rats was higher than in control rats with similar total body water content (Figure 1B), suggesting that volume-independent aspects largely contributed to salt-sensitive hypertension in both DOCA salt and DOCA-OVX rats. We quantified the relationship between rTBW and MAP (Table 2). The increase in MAP to a 1% increase in rTBW was higher in DOCA rats than in the controls and increased further with DOCA salt. DOCA-OVX salt led to similar increases in the MAP-to-volume response that were not significantly different from intact DOCA salt rats. To address volume sensitivity in more detail in DOCA salt and DOCA-OVX salt rats, we investigated the MAP/rTBW in these groups (Figure 3). Average MAP/rTBW was not different between DOCA salt and DOCA-OVX salt rats (21.20±17.80 versus 13.87±6.23; P>0.1). However, increasing rTBW decreased MAP/rTBW in DOCA salt rats, suggesting that volume sensitivity was decreased in the rats with increasing body water content to maintain blood pressure. This inverse relationship between MAP/rTBW and rTBW was perturbed in DOCA-OVX salt rats.

View larger version (17K): [in this window] [in a new window]   Figure 3. Volume sensitivity, as judged by the increase in blood pressure relative to fluid retention (MAP/rTBW; mm Hg · %WW–1) and rTBW (%WW) relationships in DOCA salt and DOCA-OVX salt rats are shown. The correlation between MAP/rTBW and rTBW was inverse in DOCA salt rats, suggesting that increases in rTBW were modulated by decreased cardiovascular volume sensitivity. This relationship was perturbed in DOCA-OVX salt rats.

	Discussion

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The important finding in our study is that DOCA salt hypertension in intact rats occurred with a TBNa⁺ excess that did not lead to a corresponding total body water excess but instead an increased susceptibility of the cardiovascular system to increase blood pressure at a given total body water content. Furthermore, the worsened hypertension with DOCA salt in OVX rats was neither attributable to significant further increases in the TBNa⁺ content nor to significant increases in the cardiovascular susceptibility to increase blood pressure at a given total body water content. Instead, the osmotically inactive Na⁺ storage capacity was reduced in DOCA salt rats with OVX. We, thus, suggest 3 distinct regulatory levels that contribute to salt-sensitive hypertension, namely: (1) Na⁺ balance sensitivity, which underscores the kidney’s role in the maintenance of TBNa⁺ homeostasis; (2) osmosensitivity, which determines whether or not a retained Na⁺ load exerts osmotic activity and, hence, increases ECV; and (3) volume sensitivity, which indicates the cardiovascular susceptibility to generate blood pressure at a given total body water content. These regulatory levels contribute individually to DOCA salt hypertension when the rats are fed a high-salt diet (Figure II, available online).

Even without unilateral nephrectomy, our model led to a failure in balance sensitivity. DOCA rats fed an 8% NaCl diet accumulated 4 mmol of Na⁺. In contrast to favored concepts of Na⁺ retention, this TBNa⁺ excess was largely compensated at the level of osmosensitivity; &80% of the sodium retention was water free. According to the traditional concept of extracellular osmotically active osmolyte retention, this Na⁺ load should lead to 27 mL of water retention. However, only 5 mL of water retention occurred, indicating that only 20% of the Na⁺ load accumulated was osmotically active. The last 80% of TBNa⁺ were accumulated water free either by osmotically inactive Na⁺ storage or by osmotically neutral Na⁺/K⁺ exchange. Water-free Na⁺ retention, thus, "buffered" the osmolyte load and rescued the rats from an 11% rTBW increase. However, although rTBW was maintained close to normal, DOCA salt rats increased blood pressure by 34 mm Hg compared with the controls. This blood pressure increase was most likely because of increased volume sensitivity of the cardiovascular system, because blood pressure was considerably higher at a given total body water content in DOCA salt rats compared with untreated controls. We imply that salt-sensitive hypertension does not primarily come about by volume-related mechanisms. Other than the renal body fluid feedback control, extrarenal body fluid regulation must play a substantial role in volume and, hence, blood pressure homeostasis in the DOCA salt model. However, because cardiovascular volume sensitivity decreased with increasing total body water content (Figure 3), we cannot precisely quantify the relative volume-dependent and volume-independent contributions to hypertension or the net-buffering effect of water-free Na⁺ retention on blood pressure.

Compared with DOCA salt rats, DOCA-OVX salt rats further increased blood pressure by 19 mm Hg, although Na⁺ retention (balance sensitivity) and the blood pressure:volume reaction (volume sensitivity) was not significantly different between intact and OVX rats. The major difference between DOCA salt rats and DOCA-OVX salt rats was found at the level of osmosensitivity. OVX reduced the osmotically inactive Na⁺ storage capacity in the rats, which increased volume retention despite similar Na⁺ retention. This finding is in line with previous experiments, where we demonstrated that OVX led to skin Na⁺ storage incapacity in rats without mineralocorticoid excess.¹⁰ However, the loss in Na⁺ storage capacity was not enough to cause a salt-sensitive blood pressure increase in untreated OVX Sprague-Dawley rats. We, thus, combined OVX and DOCA salt in this present experiment. Whereas DOCA salt rats buffered &80% of their TBNa⁺ excess by water-free Na⁺ retention, because of their loss of osmotically inactive Na⁺ storage capacity, DOCA-OVX salt rats accumulated only &67% of the retained Na⁺ load as water free. Because we found no significant differences between DOCA salt and DOCA-OVX salt rats at the level of balance sensitivity and/or volume sensitivity, we conclude that the loss in osmotically inactive Na⁺ storage capacity and the consecutive volume excess accounted for the additional 19-mm Hg blood pressure increase that was observed in DOCA-OVX salt rats.

Our findings do not necessarily contradict the findings of other investigators. The concept of renal-body fluid blood pressure feedback control in mineralocorticoid excess is based on the finding that initial Na⁺ and volume retention increases blood pressure. The resulting increase in natriuresis establishes a new steady state at increased body Na⁺ and water content at the expense of hypertension suggests an initial failure in balance sensitivity.¹¹ Other investigators showed earlier that DOCA salt increases blood pressure by increasing sympathetic nerve activity, which should increase the cardiovascular sensitivity to volume.⁸ Observations from DOCA salt mice that the blood pressure increase is caused by increased peripheral vascular resistance, rather than increased cardiac output with subsequent readjustments,¹² as well as the finding that venomotor tone is increased in DOCA salt rats,¹³ underscore the role of cardiovascular volume sensitivity in DOCA salt hypertension.

In this study, we draw attention to osmosensitivity, which can be viewed as an additional regulatory level of salt sensitivity in the DOCA salt model. The current understanding implies that Na⁺ retention invariably leads to extracellular water retention, because Na⁺ is the major cation of the extracellular space and acts to hold the extracellular volume by its osmotic activity. However, findings from long-term experiments in humans^14–18 and animals^9,19,20 suggest that Na⁺ might be accumulated without accompanying water retention, either by osmotically neutral Na⁺/K⁺ exchange or by osmotically inactive Na⁺ storage. To our knowledge, this study is the first to investigate the relationship between the internal balance of TBNa⁺ and K⁺ content, total body water content, and blood pressure in the DOCA salt model. We showed that a volume-buffering effect contained the blood pressure. The concept that osmosensitivity is an important regulatory level of salt sensitivity is underscored by our findings in DOCA-OVX salt rats, where we found no significant differences at the level of balance sensitivity and volume sensitivity but instead found major differences in the osmotically inactive Na⁺ storage capacity in OVX rats. We, thus, conclude that the loss of Na⁺ storage capacity and the consecutive increase in total body volume were responsible for the further blood pressure increase in this model of postmenopausal salt-sensitive hypertension.

Estradiol effects may decrease sympathetic nerve activity^21–23 and peripheral vascular resistance.^24–27 Female sex hormones may also influence internal Na⁺ balance by modulating osmotically inactive Na⁺ storage and thereby determining osmosensitivity of the organism during Na⁺ loading. We suggest that, in addition to the role of the kidney in the renal-body fluid feedback control system, extrarenal volume regulation by osmotically inactive Na⁺ storage and/or osmotically neutral Na⁺/K⁺ exchange also impact on long-term volume and blood pressure control, especially in postmenopausal salt-sensitive hypertension. We are aware that additional studies, including OVX with hormone replacement, must be performed, addressing these issues. Finally, we believe that our notion of water-free Na⁺ retention receives support from a recent study in marathon runners and elite athletes.²⁸ Perturbations of the serum Na⁺ concentration in these athletes could be largely explained by osmotically inactive Na⁺ storage or failure to remove Na⁺ from osmotically inactive Na⁺ reservoirs.

Perspectives
In DOCA salt rats, the skin functions as an osmotically inactive Na⁺ reservoir, and the muscle acts as an osmotically neutral Na⁺/K⁺ exchanger.⁹ The molecular mechanisms of Na⁺ storage and Na⁺/K⁺ exchange are unclear but may involve proteoglycans.²⁰ Moreover, how salt increases volume sensitivity in the organism is unclear. Possibly, neurons act as Na⁺/K⁺ exchangers during TBNa⁺ excess. Osmotically neutral Na⁺/K⁺ exchange might activate sympathetic neurons and thereby lead to hypertension without significant changes in total body fluid balance. Central nervous system osmoreceptors and Na⁺ sensors play a pivotal role in translating salt retention into central sympathetic nervous system activation.^29–32 Our model may facilitate new research avenues for salt-sensitive hypertension.

	Acknowledgments

 
Elke Prell helped with the ashing procedures. The Else Kröner-Fresenius-Stiftung and the Interdisziplinäres Zentrum für Klinische Forschung Erlangen supported the study.

Received November 29, 2005; first decision December 21, 2005; accepted March 27, 2006.

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